rs143793528

Positions:

chr19-46755791-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_024301.5(FKRP):c.341C>G(p.Ala114Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,520,312 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0092 ( 11 hom., cov: 33)

Exomes 𝑓: 0.013 ( 151 hom. )

Consequence

FKRP
NM_024301.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: 3.40

Variant links:

Genes affected

FKRP (HGNC:17997): (fukutin related protein) This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]

FKRP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_024301.5

BP4

Computational evidence support a benign effect (MetaRNN=0.008561552).

BP6

Variant 19-46755791-C-G is Benign according to our data. Variant chr19-46755791-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96108.We mark this variant Likely_benign, oryginal submissions are: {Benign=13, Likely_benign=1, Uncertain_significance=1}. Variant chr19-46755791-C-G is described in Lovd as [Pathogenic]. Variant chr19-46755791-C-G is described in Lovd as [Benign]. Variant chr19-46755791-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00923 (1405/152278) while in subpopulation NFE AF= 0.014 (951/68006). AF 95% confidence interval is 0.0132. There are 11 homozygotes in gnomad4. There are 645 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FKRP	NM_024301.5 linkuse as main transcript	c.341C>G	p.Ala114Gly	missense_variant	4/4	ENST00000318584.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FKRP	ENST00000318584.10 linkuse as main transcript	c.341C>G	p.Ala114Gly	missense_variant	4/4	1	NM_024301.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00925

AC:

1407

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.0165

Gnomad AMR

AF:

0.00910

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00745

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.0105

AC:

1313

AN:

125104

Hom.:

AF XY:

0.0107

AC XY:

729

AN XY:

68220

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00800

Gnomad ASJ exome

AF:

0.0178

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00934

Gnomad FIN exome

AF:

0.00640

Gnomad NFE exome

AF:

0.0148

Gnomad OTH exome

AF:

0.0163

GnomAD4 exome

AF:

0.0132

AC:

17997

AN:

1368034

Hom.:

151

Cov.:

AF XY:

0.0130

AC XY:

8773

AN XY:

672676

show subpopulations

Gnomad4 AFR exome

AF:

0.00186

Gnomad4 AMR exome

AF:

0.00836

Gnomad4 ASJ exome

AF:

0.0187

Gnomad4 EAS exome

AF:

0.0000845

Gnomad4 SAS exome

AF:

0.00947

Gnomad4 FIN exome

AF:

0.00752

Gnomad4 NFE exome

AF:

0.0144

Gnomad4 OTH exome

AF:

0.0116

GnomAD4 genome

AF:

0.00923

AC:

1405

AN:

152278

Hom.:

Cov.:

AF XY:

0.00866

AC XY:

645

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00233

Gnomad4 AMR

AF:

0.00908

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00746

Gnomad4 FIN

AF:

0.00640

Gnomad4 NFE

AF:

0.0140

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.0118

Hom.:

Bravo

AF:

0.00960

ESP6500AA

AF:

0.00206

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.00656

AC:

691

Asia WGS

AF:

0.00347

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 02, 2015	- -
Uncertain significance, criteria provided, single submitter	research	Center for Genetic Medicine Research, Children's National Medical Center	Dec 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -

Autosomal recessive limb-girdle muscular dystrophy type 2I

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 12, 2020	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FKRP: BS1, BS2 -

Muscular dystrophy-dystroglycanopathy type B5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Walker-Warburg congenital muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.37

.;T;T;.;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.66

T;.;T;T;T

MetaRNN

Benign

0.0072

T;T;T;T;T

MetaSVM

Pathogenic

0.92

MutationAssessor

Benign

1.4

.;L;L;.;.

MutationTaster

Benign

0.89

D;D

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.0

.;N;N;.;.

REVEL

Uncertain

0.38

Sift

Benign

0.32

.;T;T;.;.

Sift4G

Benign

0.073

T;T;T;D;D

Polyphen

0.0060

.;B;B;.;.

Vest4

0.10, 0.10

MPC

0.64

ClinPred

0.012

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.42

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over